The long-term goal of the SPORE in Soft Tissue Sarcoma is to reduce morbidity and mortality from soft tissue sarcoma by developing therapies targeted to the molecular, genetic, epigenetic, and signaling pathway alterations that are specific to sarcoma type and subtype. To pursue this, we will focus our efforts on 3 broad translational research objectives: 1. Define shared and type-specific molecular mechanisms of sarcomagenesis to identify new rational therapeutic targets, 2. Define mechanisms of resistance to targeted therapies, 3. Develop and validate targeted therapies in clinical studies. To achieve these goals we have marshaled an integrated, multidisciplinary group of basic and clinical investigators all armed with a unique resource, a clinicopathologic and outcomes database prospectively collected over a 27-year period containing data for over 8300 patients treated for soft tissue sarcoma at MSKCC. This database has been linked for the past 16 years to an institutional tissue bank, and for the past 7 years to a comprehensive tissue procurement process for establishment of primary sarcoma cell lines and mouse xenograft models of human sarcoma. The SPORE is structured around 4 research projects, 3 cores, and career development and developmental research programs. Each research project focuses on at least one of the 3 broad translational research goals listed above. RP-1 (Imatinib Resistance) aims to identify new therapeutic targets and develop new treatment strategies for pediatric and imatinib-resistant GIST. RP-2 (PDGFR/PI3K/mT0R Targeting) evaluates strategies for targeting PDGFRA signaling and reducing activated Akt in synovial sarcoma and sarcoma types that show increased expression of PDGFRA using cell lines, xenograft models, and phase II clinical trials. RP-3 (Target Discovery) aims to identify genomic drivers of oncogenesis in myxofibrosarcoma and pleomorphic malignant fibrous histiocytoma so as to identify new therapeutic targets. RP-4 (Epigenetic Therapy) aims to elucidate the epigenetic mechanisms and histone code alterations involved in the deregulation of SYT-SSX target genes in synovial sarcoma so as to enhance our understanding of synovial sarcoma pathogenesis and guide the development of new selective epigenetic therapies.